A convergent, asymmetric total synthesis of the biologically active alkaloid daphnicyclidin B is proposed. Daphnicyclidin B is a member of a larger family of structurally related daphnicyclidin alkaloids to be isolated in recent years. Many of these natural products, including daphnicyclidin B, have shown in vitro cytotoxicity against both murine lymphoma L1210 and human epidermoid carcinoma KB cell lines. The synthetically challenging fused hexacyclic ring system contains 4 stereogenic centers, a hydroxyfulvene moiety and an iminium ion and represents an exciting opportunity for methodology development to address these issues. A convergent approach is proposed for the synthesis, whereby two fragments of moderate complexity are synthesized separately and coupled together at an intermediate stage of the synthesis. A key intramolecular de Mayo cycloaddition/retro-aldol sequence will be used to generate the two fused cycloheptane rings that form the core of the molecule and install the quaternary stereocenter. Another key step in the synthesis is a palladium catalyzed "3+2" annulation sequence that will be developed to install the hydroxyfulvene moiety. PUBLIC HEALTH RELEVANCE: To date, no synthetic entry to any members of the daphnicyclidins exists and only very small quantities have been isolated from natural sources. Thus, a total synthesis of daphnicyclidin B would be an important achievement in the field of alkaloid synthesis and would also provide additional material for a more complete evaluation of its anticancer activity and therapeutic potential. The proposed synthesis also represents a general approach to many of the other daphnicyclidins.